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通讯作者:

祝之明(1962-),男,江西上饶人,博士生导师,主要从事代谢性心血管病的基础与临床研究。E-mail:zhuzm@yahoo.com

中图分类号:{Q28}

文献标识码:A

文章编号:2096-8965(2021)04-0012-07

DOI:10.12287/j.issn.2096-8965.20210402

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目录contents

    摘要

    2021年诺贝尔生理学或医学奖授予辣椒素受体TRPV1和薄荷醇感受器TRPM8通道的突破性发现,丰富了人们对热和冷触发的神经感知,及其适应环境温度机制的认识。温度敏感TRP通道——“热通道”TRPV1和“冷通道”TRPM8 不仅在神经系统有丰富表达,也存在于心血管、脂肪、肝脏和肌肉等组织器官,但其生物学意义并不清楚。为此,国内外学者探索温度敏感TRP通道调控心血管功能及糖脂代谢的作用,及其激动剂辣椒素和薄荷醇对心血管及代谢病的治疗效益。 2021年的诺贝尔奖使这个相对冷门的领域引起了较高的关注,并将推动其他多个领域的发展。

    Abstract

    The 2021 Nobel Prize in Physiology or Medicine has be awarded to the breakthrough discovery of the capsaicin receptor TRPV1 and the menthol receptors TRPM8, which enrichis people's understanding of the neural perception of heat and cold trigger and the mechanism of adaptation to ambient temperature. Temperature-sensitive TRP channels "hot channel" TRPV1 and "cold channel" TRPM8 are not only richly expressed in the nervous system, but also exist in tissues and organs such as cardiovascular, fat, liver and muscle, but their biological significance is not clear. To this end, domestic and foreign researchers explored the role of temperature sensitive TRP channel in regulating cardiovascular function and glucolipid metabolism, and the therapeutic benefits of agonists capsaicin and menthol on cardiovascular and metabolic diseases. This year's prize has brought keen attention to a relatively obscure field and will spur progress in many others.

  • 1 TRPV1和TRPM8通道的发现及生物学意义

  • 感知热和冷的能力对于生存至关重要,这是我们与周围世界互动的基础。1997年,美国科学家David·Julius发现了产生痛觉的细胞信号机制,及红辣椒和薄荷醇能激活神经系统中对热和冷产生反应的感觉受体,他利用辣椒素发现了对温度敏感的基因,这种基因编码了一种新的离子通道蛋白,将之命名为瞬时受体电位香草酸亚型1 (Transient Receptor Potential Vanilloid 1,TRPV1) [1]。TRPV1的发现是一项重大突破,为揭开其他温度感受器开辟了道路。David·Julius又使用化合物薄荷醇(men⁃ thol) 鉴定出TRPM8,这是一种被寒冷激活的感受器,它丰富了人们对感知和适应周围环境的认识。为此,David·Julius获得了2021年诺贝尔生理学或医学奖。

  • 人类的神经细胞是高度专业化的,用于检测和传导不同类型的刺激,使人们对周围环境有细微的感知,从而对周围环境做出相应的反应。近几年发现瞬时受体电位(Transient Receptor Potential,TRP) 通道是一类非选择性的阳离子通道超家族,广泛分布于哺乳动物的多种组织和细胞。根据氨基酸序列的不同TRP通道可分为6个亚家族:TRPC(canonical; TRPC1-7)、 TRPV (vanilloid; TRPV1-6)、 TRPP (polycystin;TRPP2,TRPP3,TRPP5)、TRPA (an⁃kyrin;TRPA1)、TRPML (mucolipin;TRPML1-3) 和TRPM (melastatin;TRPM1-8) [2]

  • 温度敏感TRPV1和TRPM8同其他TRP通道一样,由6个跨膜结构域,及胞内的N末端和C末端组成。靠近C末端的TM5和TM6形成离子微孔区,是决定其温度、电压和配体敏感性的关键部位。不同的温度敏感TRP通道感受温度的范围不同,温度>42℃、辣椒素、树胶脂毒素、内源性大麻素样物质和脂氧合酶产物等均可激活TRPV1通道[1, 2]。此外,pH<5.3、细胞外渗透压、细胞内游离Ca2+ 水平及胞内氧化还原状态改变等也可激活TRPV1通道。 TRPM8在8℃~28℃时被激活,形成外向整合Ca2+ 电流,当温度降低时TRPM8的活性增加。TRPM8也可被薄荷醇、冰片等冷刺激物质所激活[2]。生理情况下TRPV1和TRPM8作为感知热和冷刺激的温度通道,传导无伤害性温度刺激启动热和冷感知,从而发挥体温调节的作用。TRPV1和TRPM8还参与调控疼痛感觉,是神经性疼痛的潜在治疗靶点。

  • 2 TRPV1和TRPM8对心血管的作用

  • TRPV1和TRPM8除在神经系统表达外,在心脏、血管、内皮和脂肪等多种非神经组织中广泛表达。本团队自2004年开始,围绕温度敏感TRP通道在心血管及代谢功能调控中的作用,及其与心血管和代谢病的关联开展了系列研究 (见图1)。

  • 图1 TRPV1和TRPM8在心血管与代谢中的作用

  • 2.1 TRPV1对心血管的作用

  • TRPV1是所有TRP通道中研究较多的亚型之一。TRPV1在心脏交感传入纤维、心肌细胞和成纤维细胞均有表达。与TRPV1野生型小鼠相比较, TRPV1基因敲除小鼠冠状动脉结扎后梗死面积和死亡率增加,炎症细胞浸润、毛细血管密度和胶原含量显著升高,激活TRPV1可抑制心肌缺血损伤后梗死区域的炎症和病理性心脏重塑。TRPV1基因敲除小鼠心肌TGF-β、Smad2、VEGF和MMP2表达升高,导致心脏纤维化增加,并减少心肌保护蛋白CGRP和P物质的产生[3]。我们发现激活TRPV1可增加辣椒素敏感的神经释放CGRP和内皮细胞释放NO,降低血压。予辣椒素可快速升高血浆CGRP浓度,并伴有血压降低。辣椒素激活血管内皮TRPV1促进Ca2+ 内流,增加蛋白激酶A和eNOS的磷酸化,从而促进内皮细胞产生NO。长期予膳食辣椒素干预可增加血管eNOS磷酸化、NO生成和内皮依赖性舒张[4]。遗传性高血压大鼠予以膳食辣椒素干预可激活血管内皮TRPV1促进内皮细胞NO合成,改善血管舒张功能,降低血压[5]。TRPV1还参与高盐诱导的高血压发生,对新生幼鼠,化学损毁辣椒素敏感神经,可增加鼠成年后对盐的敏感性和血压。Dahl盐敏感大鼠TRPV1表达和功能缺失可导致高盐负荷后血压升高[6]。长期膳食辣椒素干预激活小鼠肠系膜动脉TRPV1可改善高盐摄入导致的血管内皮功能障碍及夜间血压升高[7]。此外,近几年我们还证实了中枢TRPV1通过调控摄盐行为参与血压调节,辣椒素激活TRPV1可增强中枢对盐摄入的感知[8],这种作用有助于减少高盐摄入及盐敏感性高血压的发生。

  • 2.2 TRPM8通道对心血管的作用

  • TRPM8广泛分布在血管、平滑肌和内皮等,其表达量因动物种类、年龄以及血管的类型而不同,它也存在于质膜、高尔基体和肌浆网[9, 10]。 TRPM8在人肺动脉内皮细胞中表达,其功能受损可导致肺动脉血管反应性增强[11]。在肾血管性高血压模型,血管紧张素Ⅱ (Angiotensin Ⅱ, AngⅡ) 可抑制血管平滑肌TRPM8表达,薄荷醇激活TRPM8减少AngⅡ诱导的活性氧和H2O2产生,抑制AngⅡ 诱导的NADPH氧化酶NOX1和NOX4上调[12]。 TRPM8激活可抑制Ang Ⅱ介导的RhoA相关蛋白激酶影响血管结构及功能。在肺动脉高压大鼠中,激活TRPM8可舒张肺动脉,与抑制SOCE有关[12]。TRPM8作用于GTPase Rap1可抑制内皮细胞迁移[13]

  • 我们研究发现,TRPM8在血管平滑肌细胞膜和肌浆网均有表达,长期膳食薄荷醇可激活野生型小鼠血管组织TRPM8,抑制肌浆网钙释放和RhoA/ROCK-2激酶活性及pMYPT-1表达,减少血管收缩反应,从而降低血压,但薄荷醇对TRPM8基因敲除小鼠无此作用[9]。AngⅡ和冷应激诱导的高血压小鼠显示,长期膳食薄荷醇干预通过激活肌浆网上TRPM8,抑制血管紧张素Ⅱ介导的ROS过度生成,减少细胞外Ca2+ 内流激活RhoA/ROCK-2激酶,拮抗高血压的发生[10]

  • 3 TRPV1和TRPM8对代谢器官的作用

  • 3.1 TRPV1和TRPM8在脂肪中的分布及其作用

  • 我们首先报道了TRPV1在小鼠及人白色脂肪组织 (White Adipose Tissue,WAT) 中的表达,激活脂肪细胞TRPV1增加细胞钙信号,通过抑制PPARγ和脂肪酸合酶减少脂质生成[14]。辣椒素激活脂肪TRPV1增加Cx43介导的脂肪细胞间Ca2+ 内流,从而促进脂肪分解[15]。TRPV1在棕色脂肪 (Brown Adipose Tissue, BAT) 细胞和脂肪细胞系有表达,激活TRPV1可上调产热基因表达,诱导3T3-L1前脂肪细胞分化为 “browning” 褐色脂肪表型[16]。 TRPV1还可通过控制食欲激素水平或调节胃肠道迷走神经传入信号影响食欲。辣椒素在胃肠道中可直接与TRPV1结合产生传入信号,传递至中枢神经系统下丘脑腹内侧核,促进 β2-肾上腺素受体的表达和PRDM16蛋白的产生,从而促进米色脂肪细胞的生成,增加全身能量消耗[17]。口服辣椒素可激活胃肠道内感觉神经表达的TRPV1,激活支配BAT的交感神经活性,诱导BAT的温度升高,增加全身能量消耗,降低体脂。在敲除TRPV1或UCP1基因的小鼠中,辣椒素的产热和减脂作用减弱[18],我们发现激活TRPV1增加棕色脂肪Sirt-1表达,可以促进其乙酰化和PPARγ 和PRDM-16的相互作用,增加能量消耗[19]

  • 实验证实TRPM8也在白色脂肪组织中存在,薄荷醇或Icilin激活TRPM8可诱导棕色脂肪偶联蛋白1 (Uncoupling Protein 1,UCP1) 表达。TRPM8蛋白及mRNA表达水平在脂肪细胞分化过程中显著升高,表明TRPM8在脂肪细胞的产热中有重要作用。皮肤薄荷醇处理或冷暴露导致机体核心体温升高,与UCP1表达增加有关,且这种作用是TRPM8依赖的。在冷暴露期间TRPM8基因敲除小鼠和TRPM8拮抗剂干预的野生型小鼠的核心体温降低。 TRPM8基因敲除小鼠还表现出尾部热损失增加,导致体温过低[20]。薄荷醇灌胃可增强小鼠BAT产热和WAT的“棕色化”。TRPM8基因敲除增加热量的损失和食物摄入,导致小鼠体温下降和肥胖。薄荷醇激活TRPM8诱导脂肪细胞分化和能量消耗表型,线粒体功能的相关基因表达增加[21]。TRPM8基因多态性与土耳其人群代谢综合征密切相关[22]。激活TRPM8通道可促进棕色脂肪UCP1依赖的产热和胰岛素敏感性,抑制高脂诱导的葡萄糖耐量异常和肥胖[23]。此外,TRPV1激动剂辣椒素和TRPM8激动剂薄荷醇联合应用可防止高脂诱导的体重增加,改善糖代谢和脂肪增生,促进棕色脂肪产热和糖利用,抑制脂肪和胰岛素抵抗。

  • 3.2 TRPV1与血糖稳态

  • TRPV1在大鼠胰岛 β 细胞和 β 细胞系中表达,辣椒素可剂量依赖性地增加胰岛素分泌,TRPV1拮抗剂可阻断这种作用[23, 24]。对人类的研究显示,进食辣椒素可增加血浆胰岛素水平[25]。TRPV1也存在于支配胰岛的传入感觉神经中,通过调节感觉神经调节胰岛素的分泌。辣膳食可增加人血浆胰高血糖素样肽-1 (Glucagon-Like Peptide-1,GLP-1) 水平,降低血饥饿素水平。STC-1细胞是起源于肠道的小鼠肠内分泌细胞系,在摄取营养时分泌GLP-1,我们发现TRPV1受体存在于表达GLP-1的STC-1肠细胞中,TRPV1的激活通过Ca2+ 依赖机制刺激GLP-1的释放。予辣椒素干预可促进小鼠GLP-1分泌,且这种作用能被TRPV1拮抗剂抑制,而在TRPV1基因敲除小鼠中则不显著[26]

  • 实验证实肝脏和肌肉有丰富的TRPV1表达,其参与脂肪酸氧化和糖酵解,对维持机体糖脂代谢的稳态有重要作用。辣椒素激活肝脏TRPV1可上调UCP2及过氧化物酶体增殖物激活受体δ (Peroxi⁃ some Proliferators-Activated Receptors δ, PPARδ) 表达,增强自噬作用减少肝脏细胞脂质沉积[27, 28]。辣椒素激活肌细胞TRPV1增加细胞的钙信号和过氧化物酶体增殖物激活受体-γ 共激活因子-1α (Peroxlsome Proliferator-activated Receptor-γ Coactl⁃ vator-1α,PGC-1α) 表达,上调骨骼肌的PGC1α,促进脂肪酸氧化和线粒体功能,增加慢肌纤维功能,从而增强运动耐力[29]。有报道,辣椒素激活TRPV1还可增加肌细胞CAMKK2和AMPK表达,促进肌肉葡萄糖氧化和ATP生成。

  • 3.3 TRPM8与血糖稳态

  • TRPM8也参与血糖稳态调节,给予薄荷醇或Icilin激活TRPM8可增加血清胰高血糖素的浓度,而TRPM8阻断剂可消除这种作用。长期服用薄荷醇可防止高脂饲养的动物体重增加、胰岛素抵抗,及脂肪组织增殖和肝脏甘油三酯的沉积[30]。与野生型小鼠相比较,TRPM8基因敲除小鼠的胰岛素清除率增加。肝脏无TRPM8表达,但肝脏感觉传入神经有TRPM8表达,其介导神经调控肝脏胰岛素清除[31]

  • 4 TRPV1和TRPM8功能异常与靶器官损害

  • 4.1 心肌肥厚与心肌缺血

  • 研究表明,与野生型小鼠相比较TRPV1基因敲除小鼠的心脏重量显著减少,且TRPV1基因敲除能部分预防压力负荷诱发的心脏肥大,TRPV1在主动脉结扎诱导的小鼠心肌肥厚中表达上调。我们研究表明,辣椒素激活心肌TRPV1通过改善线粒体复合酶I氧化磷酸化,拮抗高盐饮食诱导的心脏肥大[32]。TRPM8通道与心肌缺血/再灌注损伤有关。在大鼠心肌组织有TRPM8蛋白及mRNA表达,激活TRPM8可减少缺血再灌注导致的心脏梗死面积及心肌MDA和乳酸脱氢酶 (Lactate Dehydrogenase, LDH),抑制RhoA和ROCK2表达。而TRPM8拮抗剂可抑制这些作用。膳食薄荷醇干预可减轻心肌梗死损伤,降低血浆心肌肌钙蛋白I水平,减少梗死面积和胶原沉积,改善心功能和血流动力学指标,薄荷醇的这些作用是TRPM8依赖的。此外,薄荷醇干预可减少心肌梗死小鼠的炎症因子和趋化因子表达,促进降钙素基因相关肽(Calcitonin Gene-Re⁃ lated Peptide,CGRP) 的释放。

  • 4.2 肾脏损害

  • 研究表明,TRPV1在肾皮质和肾小管均有表达,激活TRPV1可提高肾小球滤过率,促进肾脏水、钠排泄。TRPV1功能障碍可导致肾脏排泄功能受损。长期高盐摄入可损伤肾皮质集合管TRPV1通道的功能,膳食辣椒素干预可激活TRPV1抑制集合管上皮钠通道的活性,减少尿钠重吸收,促进尿钠排泄,从而改善高盐诱导的血压升高[33]。线粒体钙摄入过多导致足细胞蛋白浸润功能受损是糖尿病肾病的一个重要特征。我们发现膳食辣椒素通过激活TRPV1逆转db/db或链脲佐菌素诱导的糖尿病小鼠的慢性肾脏结构和功能损伤。辣椒素激活TRPV1可以缓解高血糖诱导的足细胞线粒体功能障碍,同时减少线粒体相关膜 (MitochondriaAssociated Membranes,MAMs) 的形成,抑制从内质网到线粒体的Ca2+ 运输,其机制与TRPV1介导的Ca2+ 信号激活AMP依赖的蛋白激酶(Adenosine5'-Mo⁃ nophosphate AMP-Activated Protein Kinase,AMPK),从而减少参与MAMs形成的关键分子Fundc1的转录有关[34]。此外,激活TRPV1对缺血/再灌注急性肾损伤 (Acute Kidney Injury,AKI) 有保护作用,并可改善AKI的预后,其机制可能与支配肾脏的背根神经节的神经元TRPV1通道有关。TRPV1在慢性肾功能衰竭中的作用了解不多,但TRPV1激活对DOCA盐敏感大鼠的慢性肾纤维化有保护作用。有关TRPM8在肾脏组织中的作用尚未见报道。

  • 4.3 脑卒中

  • TRPV1激活在急性脑损伤时保持低体温是一种有效的神经保护策略,辣椒素激活TRPV1通过作用于大脑和/或周围神经元促进体温下降,在脑梗死发生前对神经起保护作用。我们发现长期膳食辣椒素激活TRPV1能增加脑基底动脉磷酸化eNOS,预防自发性高血压卒中型大鼠脑卒中的发生及增加生存时间[5]。在新生大鼠中,辣椒素干预对缺氧/缺血引起的脑损伤有神经保护作用。

  • TRPM8在脑血管和脑实质中均有表达。研究表明,低温期间软脑膜小动脉对内皮依赖性扩张剂缓激肽和谷氨酸的反应降低,而对高碳酸血症和硝普钠的反应保持不变,所有血管扩张剂反应在复温后可恢复,提示头部低温没有产生血管内皮损伤。在正常血供时TRPM8激活可使软脑膜小动脉收缩,这种作用可被TRPM8抑制剂所拮抗。头部低温可增强TRPM8介导内皮依赖性脑血管舒张功能,这对脑血管功能有保护作用。

  • 4.4 干预TRPV1和TRPM8防治心血管代谢紊乱

  • 高血压膳食疗法主要有美国膳食方法终止高血压的方案(Dietary Approaches to Stop Hypertension, DASH),强调摄入足够的蔬菜、水果、低脂 (或脱脂) 奶,以维持足够的钾、镁、钙等离子的摄取,并尽量减少饮食中盐和饱和脂肪酸[35]。欧洲的地中海式饮食方案强调多吃蔬菜、水果、鱼、海鲜、豆类、坚果类食物,其次才是谷类,并且烹饪时要用植物油 (含不饱合脂肪酸),尤其提倡用橄榄油,加上适量的红酒和大蒜[35]

  • 辣膳食的主要活性成份辣椒素可激活TRPV1发挥改善心血管及代谢的作用。荟萃分析显示,食辣可增加能量消耗 (245kJ/d),减少能量摄入 (309.9kJ/d),增加脂肪氧化,从而减轻体重和体脂。摄入辣椒素类似物也可通过激活人棕色脂肪组织增加能量代谢,减少体重[36]。此外,对近50万中国人群研究显示,中国成年人群的肥胖存在地区差异,与辛辣食物摄入有关,食辣地区的肥胖风险减少[37]。全国31个省市自治区,2亿多外卖点餐的大数据分析显示,喜辛辣食物者与发生糖尿病的风险及空腹和餐后血糖水平呈负相关[38],辛辣食物的摄入频率与发生糖尿病的死亡风险呈负相关[39],辣膳食与胰岛素抵抗有关,不食辣者胰岛素抵抗程度较重[40]。以上的调查还显示辣膳食与血压、酒精性脂肪肝和血脂水平呈负相关[41, 42],中国慢性病前瞻性研究项目 (China Kadoorie Biobank,KB) 研究显示,吃辣的频率高会显著减少缺血性心脏病、脑血管病和糖尿病的死亡风险[37]。2020年美国心脏年会报道了一项纳入美国、意大利、伊朗及中国逾57万人的人群研究,其结果显示,常吃辣者心血管死亡风险减少26%,癌症死亡风险减少23%,全因死亡风险减少25%[43]

  • TRPM8和薄荷醇对心血管代谢也有一定的益处,但人群研究证据相对较少。我们发现与安慰剂组相比较,服用8周的薄荷醇胶囊治疗可降低高血压前期个体的收缩压 (下降6mmHg) 和舒张压 (下降5mmHg),改善高血压前期个体的血管舒张功能[44]。对高血压患者和年龄匹配的血压正常的对照人群,前臂应用微透析纤维灌注不同剂量的薄荷醇,高血压组患者的前臂薄荷醇诱导的血管舒张反应减弱,NOS和感觉神经诱导的舒张功能受到抑制。有报道称,俄罗斯人群的TRPM8基因单核苷酸多态性与血总胆固醇、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇水平有关,也与甘油三酯含量和体重指数和腰臀围相关[45]。另外,已有较多研究证实降低环境温度能增加棕色脂肪的产热功能,有助于减轻体重[4647]。今后如能在前瞻性临床试验中充分证实干预TRPV1和TRPM8改善心血管及代谢的益处,将会提供一种低成本、易于推广的防治心血管和代谢病的新措施。

  • 综上所述,TRPV1和TRPM8的发现不仅揭示了机体感知温度的原理,也丰富了人们对TRPV1和TRPM8在非神经系统中的认识。我们及国内外学者的探索由“热”TRPV1做到“冷”TRPM8,将温度敏感TRP通道引入了心血管和代谢领域的工作,为心血管代谢病的防治提供了新思路。今年的诺贝尔奖使这个相对冷门的研究领域受到了热切地关注,并将推动其他多个领域的发展。

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    • [29] LUO Z D,MA L Q,ZHAO Z G,et al.TRPV1 activation improves exercise endurance and energy metabolism through PGC-1alpha upregulation in mice[J].Cell Res,2012,22(3):551-564.

    • [30] KHARE P,MANGAL P,BABOOTA R K,et al.Involvement of glucagon in preventive effect of menthol against high fat diet induced obesity in mice[J].Front Pharmacol,2018,9:1244.

    • [31] MCCOY D D,ZHOU L,NGUYEN A K,et al.Enhanced insulin clearance in mice lacking TRPM8 channels[J].Am J Physiol Endocrinol Metab,2013,305(1):E78-E88.

    • [32] LANG H,LI Q,YU H,et al.Activation of TRPV1 attenuates high salt-induced cardiac hypertrophy through improvement of mitochondrial function[J].Br J Pharmacol,2015,172(23):5548-5558.

    • [33] LI L,WANG F,WEI X,et al.Transient receptor potential vanilloid 1 activation by dietary capsaicin promotes urinary sodium excretion by inhibiting epithelial sodium channel alpha subunit-mediated sodium reabsorption[J].Hypertension,2014,64(2):397-404.

    • [34] WHITING S,DERBYSHIRE E J,TIWARI B.Could capsaicinoids help to support weight management?A systematic review and meta-analysis of energy intake data [J].Appetite,2014,73:183-188.

    • [35] ECKEL R H,JAKICIC J M,ARD J D,et al.2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[J].Circulation,2014,129(25 Suppl 2):S76-S99.

    • [36] YONESHIRO T,AITA S,KAWAI Y,et al.Nonpungent capsaicin analogs(capsinoids)increase energy expenditure through the activation of brown adipose tissue in humans[J].Am J Clin Nutr,2012,95(4):845-850.

    • [37] SUN D J,LV J,CHEN W,et al.Spicy food consumption is associated with adiposity measures among half a million Chinese people:the China Kadoorie Biobank study[J].BMC Public Health,2014,1293(14):1-10.

    • [38] ZHAO Z Y,LI M,LI C,et al.Dietary preferences and diabetic risk in China:a large-scale nationwide internet data-based study[J].J Diabetes,2020,12(4):270-278.

    • [39] LV J,QI L,YU C Q,et al.Consumption of spicy foods and total and cause specific mortality:population based cohort study[J].BMJ,2015,351:h3942.

    • [40] LI J,WANG R,XIAO C.Association between chilli food habits with iron status and insulin resistance in a Chinese population[J].J Med Food,2014,17(4):472-478.

    • [41] YUAN L J,QIN Y,WANG L,et al.Capsaicin-containing chili improved postprandial hyperglycemia,hyperinsulinemia,and fasting lipid disorders in women with gestational diabetes mellitus and lowered the Incidence of large-for-gestational-age newborns[J].Clin Nutr,2016,35(2):388-393.

    • [42] SINGH S P,SINGH A,MISRA D,et al.Risk factors associated with non-alcoholic fatty liver disease in Indians:a case-control study[J].J Clin Exp Hepatol,2015,5(4):295-302.

    • [43] YAMANI N,MUSHEER A,GOSAIN P,et al.Meta-analysis evaluating the impact of chili-pepper intake on all-cause and cardiovascular mortality:a systematic review[J].Ann Med Surg(Lond),2021,70:102774.

    • [44] SUN J,YANG T,WANG P J,et al.Activation of cold-sensing transient receptor potential melastatin subtype 8 antagonizes vasoconstriction and hypertension through attenuating RhoA/Rho kinase pathway[J].Hypertension,2014,63(6):1354-1363.

    • [45] POTAPOVA T A,BABENKO V N,KOBZEV V F,et al.Associations of cold receptor TRPM8 gene single nucleotide polymorphism with blood lipids and anthropometric parameters in Russian population[J].Bulletin of Experimental Biology and Medicine,2014,6(157):757-761.

    • [46] VAN MARKEN LICHTENBELT W D,VANHOMMERIG J W,SMULDERS N M,et al.Cold-activated brown adipose tissue in healthy men[J].N Engl J Med,2009,360(15):1500-1508.

    • [47] CLAESSENS-VAN O A,WESTERTERP K R,WOUTERS L,et al.Heat production and body temperature during cooling and rewarming in over-weight and lean men[J].Obesity,2006,14(Silver Spring):1914-1920.

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